Thumbnail - Startseite...9.7 assessment of Large Versus small Molecules in CV sP 147 9.7.1 Introduction147 9.7.2 CV sP Evaluation 147 9.8 Patients do not Necessarily Respond to Drugs

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DRUG DISCOVERY TOXICOLOGY


From Target Assessment to Translational Biomarkers

Edited by

YVOnnE WILLJ ERIC McDUFFIEAnDREW J OLAhARSkIBRAnDOn D JEFFY

Copyright copy 2016 by John Wiley amp Sons Inc All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

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Library of Congress Cataloging‐in‐Publication Data

Names Will Yvonne editorTitle Drug discovery toxicology from target assessment to translational biomarkers edited by Yvonne Will [and three others]Description Hoboken New Jersey John Wiley amp Sons Inc [2016] | Includes bibliographical references and indexIdentifiers LCCN 2015039627 (print) | LCCN 2015050089 (ebook) | ISBN 9781119053330 (cloth) | ISBN 9781119053323 (Adobe PDF) | ISBN 9781119053392 (ePub)Subjects LCSH DrugsndashToxicology | DrugsndashTesting | Toxicity testing | High throughput screening (Drug development)Classification LCC RA1238 D75 2016 (print) | LCC RA1238 (ebook) | DDC 615902ndashdc23LC record available at httplccnlocgov2015039627

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

v

LIST OF CONTRIBUTORS xxi

FOREWORD xxv

PaRT I INTRODUCTION 1

1 Emerging Technologies and their Role in Regulatory Review 3Thomas J Colatsky

11 Introduction 312 safety assessment in Drug Development and Review 4

121 Drug Discovery 4122 Preclinical Development 5

13 The Role of New Technologies in Regulatory safety assessment 6131 In Silico Models for Toxicity Prediction 6132 Cell‐Based assays for Toxicity Prediction 7

14 Conclusions 8References 8

PaRT II SaFETY LEaD OPTIMIZaTION STRaTEGIES 13

2 Small‐Molecule Safety Lead Optimization 15Donna M Dambach

21 Background and Objectives of safety Lead Optimization approaches 1522 Target safety assessments Evaluation of Undesired Pharmacology and

Therapeutic area Considerations 1623 Implementing Lead Optimization strategies for small Molecules 16

231 strategic approach 17232 application of Prospective Models 17233 application of Retrospective Models 22


CONTENTS

vi CONTENTs

3 Safety assessment Strategies and Predictive Safety of Biopharmaceuticals and antibody Drug Conjugates 27Michelle J Horner Mary Jane Hinrichs and Nicholas Buss

31 Background and Objectives 2732 Target safety assessments strategies to Understand Target Biology

and associated Liabilities 28321 Target safety assessment for Biopharmaceuticals Targeting

the Immune system 2833 strategic approaches for Biopharmaceuticals and aDCs 29

331 Modality‐associated Risks 29332 mabs 29333 aDCs 30334 On‐Target Toxicity 30335 Off‐Target Toxicity 32336 Evaluation of Novel Warheads 32337 Evaluation of New aDC Technologies 33

34 Predictive safety Tools for Large Molecules 33341 Immunogenicity 33342 specialized assays for Detection of aDCC CDC and aDCP 33343 Immunotoxicity Testing 34344 Predicting and assessing Unintended adverse Consequences 34

35 strategies for species selection 3436 strategy for Dose‐Ranging studies for safety Evaluation of Biopharmaceuticals 3537 Conclusions 35References 36

4 Discovery and Development Strategies for Small Interfering RNas 39Scott A Barros and Gregory Hinkle

41 Background 39411 RNai Molecular Mechanism 39412 Conjugate siRNas for Hepatic Targets 39

42 Target assessments 40421 Large Gene Families 40422 short Transcripts 40423 Genes with Rapid mRNa Turnover 40424 selecting among alternate Transcript Variants 41

43 siRNa Design and screening strategies 41431 siRNa Design 41432 Chemical Modification of siRNa 42433 screening of siRNa Therapeutics 42

44 safety Lead Optimization of siRNa 45441 Immunostimulation screening 45442 Toxicology screening in Rodents 46443 Points to Consider for Chemically Modified Nucleotides 47

45 Integration of Lead Optimization Data for Candidate selection and Development 4846 Conclusions 49References 49

PaRT III BaSIS FOR IN VITROndashIN VIVO PK TRaNSLaTION 53

5 Physicochemistry and the Off‐Target Effects of Drug Molecules 55Dennis A Smith

51 Lipohilicity Polar surface area and Lipoidal Permeability 5552 Physicochemistry and Basic aDME Properties for High Lipoidal

Permeability Drugs 56

CONTENTs vii

53 Relationship between Volume of Distribution (Vd) and Target access

for Passively Distributed Drugs 5854 Basicity Lipophilicity and Volume of Distribution as a Predictor

of Toxicity (T) adding The T to aDMET 5955 Basicity and Lipophilicity as a Predictor of Toxicity (T)

separating the D from T in aDMET 6056 Lipophilicity and Psa as a Predictor of Toxicity (T) adding the T to aDMET 6057 Metabolism and Physicochemical Properties 6158 Concentration of Compounds by Transporters 6159 Inhibition of Excretion Pumps 63510 Conclusions 64References 65

6 The Need for Human Exposure Projection in the Interpretation of Preclinical In Vitro and In Vivo aDME Tox Data 67Patrick Poulin

61 Introduction 6762 Methodology Used for Human PK Projection in Drug Discovery 67

621 Prediction of Plasma ConcentrationndashTime Profile by Using the Wajima allometric Method 68

622 Prediction of Plasma and Tissue ConcentrationndashTime Profiles by Using the PBPK Modeling approach 68

623 Integrative approaches of Toxicity Prediction Based on the Extent of Target Tissue Distribution 70

63 summary of the Take‐Home Messages from the Pharmaceutical Research and Manufacturers of america CPCDC Initiative on Predictive Models of Human PK from 2011 72631 PhRMa Initiative on the Prediction of CL 75632 PhRMa Initiative on the Prediction of Volume of Distribution 75633 PhRMa Initiative on the Prediction of ConcentrationndashTime Profile 75634 Lead Commentaries on the PhRMa Initiative 76

References 77

7 aDME Properties Leading to Toxicity 82Katya Tsaioun

71 Introduction 8272 The science of aDME 8373 The aDME Optimization strategy 8374 Conclusions and Future Directions 89References 90

PaRT IV PREDICTING ORGaN TOxICITY 93

8 Liver 95J Gerry Kenna Mikael Persson Scott Q Siler Ke Yu Chuchu Hu Minjun Chen Joshua Xu Weida Tong Yvonne Will and Michael D Aleo

81 Introduction 9582 DILI Mechanisms and susceptibility 9683 Common Mechanisms that Contribute to DILI 98

831 Mitochondrial Injury 98832 Reactive Metabolite‐Mediated Toxicity 100833 BsEP Inhibition 102834 Complicity between Dual Inhibitors of BsEP

and Mitochondrial Function 10584 Models systems Used to study DILI 108

viii CONTENTs

841 High Content Image analysis 108842 Complex Cell Models 110843 Zebrafish 111

85 In Silico Models 11486 systems Pharmacology and DILI 11887 summary 119References 121

9 Cardiac 130David J Gallacher Gary Gintant Najah Abi‐Gerges Mark R Davies Hua Rong Lu Kimberley M Hoagland Georg Rast Brian D Guth Hugo M Vargas and Robert L Hamlin

91 General Introduction 13092 Classical In VitroEx Vivo assessment of Cardiac Electrophysiologic Effects 133

921 Introduction 133922 subcellular Techniques 134923 Ionic Currents 134924 aPRepolarization assays 135925 Proarrhythmia assays 136926 Future Directions stem Cell‐Derived CMs 136927 Conclusions 136

93 Cardiac Ion Channels and In Silico Prediction 137931 Introduction 137932 High‐Throughput Cardiac Ion Channel Data 137932 In Silico approaches 137

94 From animal Ex VivoIn Vitro Models to Human stem Cell‐Derived CMs for Cardiac safety Testing 140941 Introduction 140942 Currently available Technologies 140943 Conclusions 141

95 In Vivo Telemetry Capabilities and Preclinical Drug Development 141951 Introduction 141952 CV sP Evaluations Using Telemetry 142953 Evaluation of Respiratory Function Using Telemetry 143954 Evaluation of CNs Using Telemetry 143955 Evaluation of Other systems Using Telemetry 143

96 assessment of Myocardial Contractility in Preclinical Models 144961 Introduction 144962 Gold standard approaches 144963 In Vitro and Ex Vivo assays 145964 In Vivo assays 145965 Translation to Clinic 146

97 assessment of Large Versus small Molecules in CV sP 147971 Introduction 147972 CV sP Evaluation 147

98 Patients do not Necessarily Respond to Drugs and Devices as do Genetically Identical Young Mature Healthy Mice 148981 Conclusions 152

References 152

10 Predictive In Vitro Models for assessment of Nephrotoxicity and DrugndashDrug Interactions In Vitro 160Lawrence H Lash

101 Introduction 1601011 Considerations for studying the Kidneys as a Target

Organ for Drugs and Toxic Chemicals 160

CONTENTs ix

1012 advantages and Limitations of In Vitro Models in General for Mechanistic Toxicology and screening of Potential adverse Effects 161

1013 Types of In Vitro Models available for studying Human Kidneys 162102 Biological Processes and Toxic Responses of the Kidneys that are

Normally Measured in Toxicology Research and Drug Development studies 163

103 Primary Cultures of hPT Cells 1641031 Methods for hPT Cell Isolation 1641032 Validation of hPT Primary Cell Cultures 1651033 advantages and Limitations of hPT Primary Cell Cultures 1651034 Genetic Polymorphisms and Interindividual susceptibility 166

104 Toxicology studies in hPT Primary Cell Cultures 166105 Critical studies for Drug Discovery in hPT Primary Cell Cultures 168

1051 Phase I and Phase II Drug Metabolism 1681052 Membrane Transport 168

106 summary and Conclusions 1681061 advantages and Limitations of Performing studies

in hPT Primary Cell Cultures 1681062 Future Directions 169

References 170

11 Predicting Organ Toxicity In Vitro Bone Marrow 172Ivan Rich and Andrew J Olaharski

111 Introduction 172112 Biology of the Hematopoietic system 172113 Hemotoxicity 173114 Measuring Hemotoxicity 173

1141 Uses of the CFC assay 1731142 In VitroIn Vivo Concordance 1751143 Limitations of the CFC assay 175

115 The Next Generation of assays 175116 Proliferation or Differentiation 175117 Measuring and Predicting Hemotoxicity In Vitro 176118 Detecting stem and Progenitor Cell Downstream Events 177119 Bone Marrow Toxicity Testing During Drug Development 1771110 Paradigm for In Vitro Hemotoxicity Testing 1781111 Predicting starting Doses for animal and Human Clinical Trials 1791112 Future Trends 1791113 Conclusions 180References 180

12 Predicting Organ Toxicity In Vitro Dermal Toxicity 182Patrick J Hayden Michael Bachelor Mitchell Klausner and Helena Kandaacuterovaacute

121 Introduction 182122 Overview of Drug‐Induced adverse Cutaneous Reactions 182123 Overview of In Vitro skin Models with Relevance to

Preclinical Drug Development 183124 specific applications of In Vitro skin Models and Predictive

In Vitro assays Relevant to Pharmaceutical Development 1841241 skin sensitization 1841242 Phototoxicity 1851243 skin Irritation 187

125 Mechanism‐Based Cutaneous adverse Effects 1871251 Percutaneous absorption 187

x CONTENTs

1252 Genotoxicity 1881253 skin LighteningMelanogenesis 188

126 summary 188References 189

13 In Vitro Methods in Immunotoxicity assessment 193Xu Zhu and Ellen Evans

131 Introduction and Perspectives on In Vitro Immunotoxicity screening 193132 Overview of the Immune system 194133 Examples of In Vitro approaches 196

1331 acquired Immune Responses 1961332 Fcγ Receptor and Complement Binding 1961333 assessment of Hypersensitivity 1961334 Immunogenicity of Biologics 1981335 Immunotoxicity Due to Myelotoxicity 198


14 Strategies and assays for Minimizing Risk of Ocular Toxicity during Early Development of Systemically administered Drugs 201Chris J Somps Paul Butler Jay H Fortner Keri E Cannon and Wenhu Huang

141 Introduction 201142 In Silico and In Vitro Tools and strategies 201143 Higher‐Throughput In Vivo Tools and strategies 202

1431 Ocular Reflexes and associated Behaviors 2021432 Noninvasive Ophthalmic Examinations 206

144 strategies Gaps and Emerging Technologies 2081441 strategic Deployment of In Silico In Vitro and In Vivo Tools 2081442 Emerging Biomarkers of Retinal Toxicity 210


15 Predicting Organ Toxicity In VivomdashCentral Nervous System 214Greet Teuns and Alison Easter

151 Introduction 214152 Models for assessment of CNs aDRs 214

1521 In Vivo Behavioral Batteries 2141522 In Vitro Models 215

153 seizure Liability Testing 2161531 Introduction 2161532 MediumHigh Throughput approaches to assess

seizure Liability of Drug Candidates 2161533 In Vivo approaches to assess seizure Liability of Drug

Candidates 217154 Drug abuse Liability Testing 218

1541 Introduction 2181542 Preclinical Models to Test abuse Potential of CNs‐active

Drug Candidates 219155 General Conclusions 222

1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi

16 Biomarkers Cell Models and In Vitro assays for Gastrointestinal Toxicology 227Allison Vitsky and Gina M Yanochko

161 Introduction 227162 anatomic and Physiologic Considerations 228

1621 Oral Cavity 2281622 Esophagus 2281623 stomach 2281624 small and Large Intestine 229

163 GI Biomarkers 2291631 Biomarkers of Epithelial Mass Intestinal Function

or Cellular Damage 2291632 Biomarkers of Inflammation 230

164 Cell Models of the GI Tract 2311641 Cell Lines and Primary Cells 2311642 Induced Pluripotent stem Cells 2321643 Coculture systems 2321644 3D Organoid Models 2331645 Organs‐on‐a‐Chip 235

165 Cell‐Based In Vitro assays for screening and Mechanistic Investigations to GI Toxicity 2351651 Cell Viability 2361652 Cell Migration 2361653 Barrier Integrity 236

166 summaryConclusionsChallenges 236References 236

17 Preclinical Safety assessment of Drug Candidate‐Induced Pancreatic Toxicity From an applied Perspective 242Karrie A Brenneman Shashi K Ramaiah and Lauren M Gauthier

171 Drug‐Induced Pancreatic Toxicity 2421711 Introduction 2421712 Drug‐Induced Pancreatic Exocrine Toxicity in Humans

Pancreatitis 2431713 Mechanisms of Drug‐Induced Pancreatic Toxicity 244

172 Preclinical Evaluation of Pancreatic Toxicity 2451721 Introduction 2451722 Risk Management and Understanding the Potential

for Clinical Translation 2451723 Interspecies and Interstrain Differences in susceptibility

to Pancreatic Toxicity 246173 Preclinical Pancreatic Toxicity assessment In Vivo 247

1731 Routine assessment 2471732 specialized Techniques 248

174 Pancreatic Biomarkers 2491741 Introduction 2491742 Exocrine Injury Biomarkers in Humans and Preclinical species 2501743 EndocrineIslet Functional Biomarkers for Humans and

Preclinical species 2521744 a Note on Biomarkers of Vascular Injury Relevant

to the Pancreas 2531745 authorrsquos Opinion on the strategy for Investments to address

Pancreatic Biomarker Gaps 253

xii CONTENTs

175 Preclinical Pancreatic Toxicity assessment In Vitro 2531751 Introduction to Pancreatic Cell Culture 2531752 Modeling In Vitro Toxicity In Vitro Testing Translatability

and In Vitro screening Tools 2541753 Case study 1 Drug Candidate‐Induced Direct acinar Cell

Toxicity In Vivo with Confirmation of Toxicity and Drug Candidate screening In Vitro 255

1754 Case study 2 Drug Candidate‐Induced Microvascular Injury at the ExocrinendashEndocrine Interface in the Rat with Unsuccessful Confirmation of Toxicity In Vitro and No Pancreas‐specific Monitorable Biomarkers Identified 256

1755 Emerging TechnologiesGaps Organotypic Models 256176 summary and Conclusions 257acknowledgments 258References 258

PaRT V aDDRESSING THE FaLSE NEGaTIVE SPaCEmdashINCREaSING PREDICTIVITY 261

18 animal Models of Disease for Future Toxicity Predictions 263Sherry J Morgan and Chandikumar S Elangbam

181 Introduction 263182 Hepatic Disease Models 264

1821 Hepatic Toxicity Relevance to Drug attrition 2641822 Hepatic Toxicity Reasons for Poor Translation from animal

to Human 2641823 available Hepatic Models to Predict Hepatic Toxicity

or Understand Molecular Mechanisms of Toxicity advantages and Limitations 264

183 Cardiovascular Disease Models 2681831 Cardiac Toxicity Relevance to Drug attrition 2681832 Cardiac Toxicity Reasons for Poor Translation from

animal to Human 2681833 available CV Models to Predict Cardiac Toxicity


184 Nervous system Disease Models 2701841 Nervous system Toxicity Relevance to Drug attrition 2701842 Nervous system Toxicity Reasons for Poor Translation

from animal to Human 2701843 available Nervous system Models to Predict Nervous system

Toxicity or Understand Molecular Mechanisms of Toxicity advantages and Limitations 270

185 Gastrointestinal Injury Models 2731851 Gastrointestinal (GI) Toxicity Relevance to Drug attrition 2731852 Gastrointestinal Toxicity Reasons for Poor Translation

from animal to Human 2731853 available Gastrointestinal animal Models to Predict

Gastrointestinal Toxicity or Understand Molecular Mechanisms of Toxicity advantages and Limitations 274

186 Renal Injury Models 2791861 Renal Toxicity Relevance to Drug attrition 2791862 Renal Toxicity Reasons for Poor Translation from

animal to Human 279

CONTENTs xiii

1863 available Renal Models to Predict Renal Toxicity or Understand Molecular Mechanisms of Toxicity advantages and Limitations 280

187 Respiratory Disease Models 2821871 Respiratory Toxicity Relevance to Drug attrition 2821872 Respiratory Toxicity Reasons for adequate Translation

from animal to Human 2821873 available Respiratory Models to Predict Respiratory Toxicity


188 Conclusion 285References 287

19 The Use of Genetically Modified animals in Discovery Toxicology 298Dolores Diaz and Jonathan M Maher

191 Introduction 298192 Large‐scale Gene Targeting and Phenotyping Efforts 299193 Use of Genetically Modified animal Models in Discovery Toxicology 300194 The Use of Genetically Modified animals in Pharmacokinetic and

Metabolism studies 3031941 Drug Metabolism 3031942 Drug Transporters 3061943 Nuclear Receptors and Coordinate Induction 3071944 Humanized Liver Models 308


20 Mouse Population-Based Toxicology for Personalized Medicine and Improved Safety Prediction 314Alison H Harrill

201 Introduction 314202 Pharmacogenetics and Population Variability 314203 Rodent Populations Enable a Population‐Based approaches

to Toxicology 3162031 Mouse Diversity Panel 3172032 CC Mice 3182033 DO Mice 319

204 applications for Pharmaceutical safety science 3202041 Personalized Medicine Development of Companion

Diagnostics 3202042 Biomarkers of sensitivity 3202043 Mode of action 322

205 study Design Considerations for Genomic Mapping 3222051 Dose selection 3222052 Model selection 3222053 sample size 3232054 Phenotyping 3242055 Genome‐Wide association analysis 3242056 Candidate Gene analysis 3242057 Cost Considerations 3252058 Health status 325


xiv CONTENTs

PaRT VI STEM CELLS IN TOxICOLOGY 331

21 application of Pluripotent Stem Cells in Drug‐Induced Liver Injury Safety assessment 333Christopher S Pridgeon Fang Zhang James A Heslop Charlotte ML Nugues Neil R Kitteringham B Kevin Park and Christopher EP Goldring

211 The Liver Hepatocytes and Drug‐Induced Liver Injury 333212 Current Models of DILI 334

2121 Primary Human Hepatocytes 3342122 Murine Models 3362123 Cell Lines 3362124 stem Cell Models 337

213 Uses of iPsC HLCs 338214 Challenges of Using iPsCs and New Directions for Improvement 339

2141 Complex Culture systems 3402142 Coculture 3402143 3D Culture 3402144 Perfusion Bioreactors 341

215 alternate Uses of HLCs in Toxicity assessment 341References 342

22 Human Pluripotent Stem Cell‐Derived Cardiomyocytes a New Paradigm in Predictive Pharmacology and Toxicology 346Praveen Shukla Priyanka Garg and Joseph C Wu

221 Introduction 346222 advent of hPsCs Reprogramming and Cardiac Differentiation 347

2221 Reprogramming 3472222 Cardiac Differentiation 347

223 iPsC‐Based Disease Modeling and Drug Testing 349224 Traditional Target‐Centric Drug Discovery Paradigm 354225 iPsC‐Based Drug Discovery Paradigm 354

2251 Target Identification and Validation ldquoClinical Trial in a Dishrdquo 3562252 safety Pharmacology and Toxicological Testing 356

226 Limitations and Challenges 358227 Conclusions and Future Perspective 359acknowledgments 360References 360

23 Stem Cell‐Derived Renal Cells and Predictive Renal In Vitro Models 365Jacqueline Kai Chin Chuah Yue Ning Lam Peng Huang and Daniele Zink

231 Introduction 365232 Protocols for the Differentiation of Pluripotent stem Cells into

Cells of the Renal Lineage 3672321 Earlier Protocols and the Recent Race 3672322 Protocols Designed to Mimic Embryonic Kidney Development 3692323 Rapid and Efficient Methods for the Generation of Proximal

Tubular‐Like Cells 372233 Renal In Vitro Models for Drug safety screening 376

2331 Microfluidic and 3D Models and Other Models that have been Tested with Lower Numbers of Compounds 376

2332 In Vitro Models that have been Tested with Higher Numbers of Compounds and the First Predictive Renal In Vitro Model 376

2333 stem Cell‐Based Predictive Models 377

CONTENTs xv

234 achievements and Future Directions 378acknowledgments 379Notes 379References 379

PaRT VII CURRENT STaTUS OF PRECLINICaL IN VIVO TOxICITY BIOMaRKERS 385

24 Predictive Cardiac Hypertrophy Biomarkers in Nonclinical Studies 387Steven K Engle

241 Introduction to Biomarkers 387242 Cardiovascular Toxicity 387243 Cardiac Hypertrophy 388244 Diagnosis of Cardiac Hypertrophy 389245 Biomarkers of Cardiac Hypertrophy 389246 Case studies 392247 Conclusion 392References 393

25 Vascular Injury Biomarkers 397Tanja S Zabka and Kaiumldre Bendjama

251 Historical Context of Drug‐Induced Vascular Injury and Drug Development 397

252 Current state of DIVI Biomarkers 398253 Current status and Future of In Vitro systems to

Investigate DIVI 402254 Incorporation of In Vitro and In Vivo Tools in Preclinical

Drug Development 403255 DIVI Case study 403References 403

26 Novel Translational Biomarkers of Skeletal Muscle Injury 407Peter M Burch and Warren E Glaab

261 Introduction 407262 Overview of Drug‐Induced skeletal Muscle Injury 407263 Novel Biomarkers of Drug‐Induced skeletal Muscle

Injury 4092631 skeletal Troponin I (sTnI) 4092632 Creatine Kinase M (CKM) 4092633 Myosin Light Chain 3 (Myl3) 4092634 Fatty acid‐Binding Protein 3 4102635 Parvalbumin 4102636 Myoglobin 4102637 MicroRNas 410

264 Regulatory Endorsement 411265 Gaps and Future Directions 411266 Conclusions 412References 412

xvi CONTENTs

27 Translational Mechanistic Biomarkers and Models for Predicting Drug‐Induced Liver Injury Clinical to In Vitro Perspectives 416Daniel J Antoine

271 Introduction 416272 Drug‐Induced Toxicity and the Liver 417273 Current status of Biomarkers for the assessment of DILI 418274 Novel Investigational Biomarkers for DILI 419

2741 Glutamate Dehydrogenase 4192742 acylcarnitines 4202743 High‐Mobility Group Box‐1 (HMGB1) 4202744 Keratin‐18 (K18) 4212745 MicroRNa‐122 (miR‐122) 421

275 In Vitro Models and the Prediction of Human DILI 422276 Conclusions and Future Perspectives 423References 424

PaRT VIII KIDNEY INjURY BIOMaRKERS 429

28 assessing and Predicting Drug‐Induced Kidney Injury Functional Change and Safety in Preclinical Studies in Rats 431Yafei Chen

281 Introduction 431282 Kidney Functional Biomarkers (Glomerular Filtration and Tubular

Reabsorption) 4332821 Traditional Functional Biomarkers 4332822 Novel Functional Biomarkers 434

283 Novel Kidney Tissue Injury Biomarkers 4352831 Urinary N‐acetyl‐β‐d‐Glucosaminidase (NaG) 4352832 Urinary Glutathione S‐Transferase α (α‐GsT) 4352833 Urinary Renal Papillary antigen 1 (RPa‐1) 4352834 Urinary Calbindin D28 435

284 Novel Biomarkers of Kidney Tissue stress Response 4362841 Urinary Kidney Injury Molecule‐1 (KIM‐1) 4362842 Urinary Clusterin 4362843 Urinary Neutrophil Gelatinase‐associated Lipocalin (NGaL) 4362844 Urinary Osteopontin (OPN) 4372845 Urinary l‐Type Fatty acid‐Binding Protein (l‐FaBP) 4372846 Urinary Interleukin‐18 (IL‐18) 437

285 application of an Integrated Rat Platform (automated Blood sampling and Telemetry aBsT) for Kidney Function and Injury assessment 437

References 439

29 Canine Kidney Safety Protein Biomarkers 443Manisha Sonee

291 Introduction 443292 Novel Canine Renal Protein Biomarkers 443293 Evaluations of Novel Canine Renal Protein Biomarker Performance 444294 Conclusion 444References 445

CONTENTs xvii

30 Traditional Kidney Safety Protein Biomarkers and Next‐Generation Drug‐Induced Kidney Injury Biomarkers in Nonhuman Primates 446Jean‐Charles Gautier and Xiaobing Zhou

301 Introduction 446302 Evaluations of Novel NHP Renal Protein Biomarker Performance 447303 New Horizons Urinary MicroRNas and Nephrotoxicity in NHPs 447References 447

31 Rat Kidney MicroRNa atlas 448Aaron T Smith

311 Introduction 448312 Key Findings 448References 449

32 MicroRNas as Next‐Generation Kidney Tubular Injury Biomarkers in Rats 450Heidrun Ellinger‐Ziegelbauer and Rounak Nassirpour

321 Introduction 450322 Rat Tubular miRNas 450323 Conclusions 451References 451

33 MicroRNas as Novel Glomerular Injury Biomarkers in Rats 452Rachel Church

331 Introduction 452332 Rat Glomerular miRNas 452References 453

34 Integrating Novel Imaging Technologies to Investigate Drug‐Induced Kidney Toxicity 454Bettina Wilm and Neal C Burton

341 Introduction 454342 Overviews 455343 summary 456References 456

35 In Vitro to In Vivo Relationships with Respect to Kidney Safety Biomarkers 458Paul Jennings

351 Renal Cell Lines as Tools for Toxicological Investigations 458352 Mechanistic approaches and In Vitro to In Vivo Translation 459353 Closing Remarks 460References 460

36 Case Study Fully automated Image analysis of Podocyte Injury Biomarker Expression in Rats 462Jing Ying Ma

361 Introduction 462362 Material and Methods 462363 Results 463364 Conclusions 465References 465

xviii CONTENTs

37 Case Study Novel Renal Biomarkers Translation to Humans 466Deborah A Burt

371 Introduction 466372 Implementation of Translational Renal Biomarkers

in Drug Development 466373 Conclusion 467References 467

38 Case Study MicroRNas as Novel Kidney Injury Biomarkers in Canines 468Craig Fisher Erik Koenig and Patrick Kirby


39 Novel Testicular Injury Biomarkers 471Hank Lin

391 Introduction 471392 The Testis 471393 Potential Biomarkers for Testicular Toxicity 472

3931 Inhibin B 4723932 androgen‐Binding Protein 4723933 sP22 4723934 Emerging Novel approaches 472


PaRT Ix BEST PRaCTICES IN BIOMaRKER EVaLUaTIONS 475

40 Best Practices in Preclinical Biomarker Sample Collections 477Jaqueline Tarrant

401 Considerations for Reducing Preanalytical Variability in Biomarker Testing 477402 Biological sample Matrix Variables 477403 Collection Variables 480404 sample Processing and storage Variables 480References 480

41 Best Practices in Novel Biomarker assay Fit‐for‐Purpose Testing 481Karen M Lynch

411 Introduction 481412 Why Use a Fit‐for‐Purpose assay 481413 Overview of Fit‐for‐Purpose assay Method Validations 482414 assay Method suitability in Preclinical studies 482415 Best Practices for analytical Methods Validation 482

4151 assay Precision 4824152 accuracyRecovery 4844153 Precision and accuracy of the Calibration Curve 4844154 Lower Limit of Quantification 4844155 Upper Limit of Quantification 4844156 Limit of Detection 485

CONTENTs xix

4157 Precision assessment for Biological samples 4854158 Dilutional Linearity and Parallelism 4854159 Quality Control 486

416 species‐ and Gender‐specific Reference Ranges 486417 analyte stability 487418 additional Method Performance Evaluations 487References 487

42 Best Practices in Evaluating Novel Biomarker Fit for Purpose and Translatability 489Amanda F Baker

421 Introduction 489422 Protocol Development 489423 assembling an Operations Team 489424 Translatable Biomarker Use 490425 assay selection 490426 Biological Matrix selection 490427 Documentation of Patient Factors 491428 Human sample Collection Procedures 491

4281 Biomarkers in Human Tissue Biopsy and Biofluid samples 491

429 Choice of Collection Device 4914291 Tissue Collection Device 4914292 Plasma Collection Device 4924293 serum Collection Device 4924294 Urine Collection Device 492

4210 schedule of Collections 4924211 Human sample Quality assurance 492

42111 Monitoring Compliance to sample Collection Procedures 492

42112 Documenting Time and Temperature from sample Collection to Processing 492

42113 Optimal Handling and Preservation Methods 49242114 Choice of sample storage Tubes 49342115 Choice of sample Labeling 49342116 Optimal sample storage Conditions 493

4212 Logistics Plan 4934213 Database Considerations 4934214 Conclusive Remarks 493References 493

43 Best Practices in Translational Biomarker Data analysis 495Robin Mogg and Daniel Holder

431 Introduction 495432 statistical Considerations for Preclinical studies of safety

Biomarkers 496433 statistical Considerations for Exploratory Clinical studies

of Translational safety Biomarkers 497434 statistical Considerations for Confirmatory Clinical studies

of Translational safety Biomarkers 498435 summary 498References 498

xx CONTENTs

44 Translatable Biomarkers in Drug Development Regulatory acceptance and Qualification 500John‐Michael Sauer Elizabeth G Walker and Amy C Porter

441 safety Biomarkers 500442 Qualification of safety Biomarkers 501443 Letter of support for safety Biomarkers 502444 Critical Path Institutersquos Predictive safety Testing Consortium 502445 Predictive safety Testing Consortium and its Key Collaborations 504446 advancing the Qualification Process and Defining Evidentiary standards 505References 506

PaRT x CONCLUSIONS 509

45 Toxicogenomics in Drug Discovery Toxicology History Methods Case Studies and Future Directions 511Brandon D Jeffy Joseph Milano and Richard J Brennan

451 a Brief History of Toxicogenomics 511452 Tools and strategies for analyzing Toxicogenomics Data 513453 Drug Discovery Toxicology Case studies 519

4531 Case studies Diagnostic Toxicogenomics 5204532 Case studies Predictive Toxicogenomics 5214533 Case studies MechanisticInvestigative Toxicogenomics 5234534 Future Directions in Drug Discovery Toxicogenomics 524

References 525

46 Issue Investigation and Practices in Discovery Toxicology 530Dolores Diaz Dylan P Hartley and Raymond Kemper

461 Introduction 530462 Overview of Issue Investigation in the Discovery space 530463 strategies to address Toxicities in the Discovery space 532464 Cross‐Functional Collaborative Model 533465 Case‐studies of Issue Resolution in The Discovery space 536466 Data Inclusion in Regulatory Filings 538References 538

aBBREVIaTIONS 540

CONCLUDING REMaRKS 542

INDEx 543

xxi

Najah Abi‐Gerges AnaBios Corporation San Diego CA USA

Michael D Aleo Investigative Toxicology Drug Safety Research and Development Pfizer Inc Groton CT USA

Daniel J Antoine MRC Centre for Drug Safety Science and Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Michael Bachelor MatTek Corporation Ashland MA USA

Amanda F Baker Arizona Health Sciences Center University of Arizona Tucson AZ USA

Scott A Barros Investigative Toxicology Alnylam Pharmashyceuticals Inc Cambridge MA USA

Kaiumldre Bendjama Transgene Illkirch‐Graffenstaden France

Eric AG Blomme AbbVie Pharmaceutical Research amp Development North Chicago IL USA

Richard J Brennan Preclinical Safety Sanofi SA Waltham MA USA

Karrie A Brenneman Toxicologic Pathology Drug Safety Research and Development Pfizer Inc Andover MA USA

Peter M Burch Investigative Pathology Drug Safety Research and Development Pfizer Inc Groton CT USA

Deborah A Burt Biomarker Development and Translation Drug Safety Research and Development Pfizer Inc Groton CT USA

Neal C Burton iThera Medical GmbH Munich Germany

Nicholas Buss Biologics Safety Assessment MedImmune Gaithersburg MD USA

Paul Butler Global Safety Pharmacology Drug Safety Research and Development Pfizer Inc La Jolla CA USA

Keri E Cannon Toxicology Halozyme Therapeutics Inc San Diego CA USA

Minjun Chen Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration (NCTRFDA) Jefferson AZ USA

Yafei Chen Mechanistic amp Investigative Toxicology Discovery Sciences Janssen Research amp Development LLC San Diego CA USA

Jacqueline Kai Chin Chuah Institute of Bioengineering and Nanotechnology The Nanos Singapore

Rachel Church University of North Carolina Institute for Drug Safety Sciences Chapel Hill NC USA

Thomas J Colatsky Division of Applied Regulatory Science Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA

Donna M Dambach Safety Assessment Genentech Inc South San Francisco CA USA

Mark R Davies QT‐Informatics Limited Macclesfield England

Dolores Diaz Discovery Toxicology Safety Assessment Genentech Inc South San Francisco CA USA

Alison Easter Biogen Inc Cambridge MA USA

LIST OF CONTRIBUTORS

xxii LIST OF CONTRIBUTORS

Heidrun Ellinger‐Ziegelbauer Investigational Toxicology GDD‐GED‐Toxicology Bayer Pharma AG Wuppertal Germany

Chandikumar S Elangbam Pathophysiology Safety Assessment GlaxoSmithKline Research Triangle Park NC USA

Steven K Engle Lilly Research Laboratories Division of Eli Lilly and Company Lilly Corporate Center Indianapolis IN USA

Ellen Evans Immunotoxicology Center of Emphasis Drug Safety Research and Development Pfizer Inc Groton CT USA

Craig Fisher Drug Safety Evaluation Takeda California Inc San Diego CA USA

Jay H Fortner Veterinary Science amp Technology Comparative Medicine Pfizer Inc Groton CT USA

David J Gallacher Global Safety Pharmacology Janssen Research amp Development a division of Janssen Pharmaceutica NV Beerse Belgium

Priyanka Garg Stanford Cardiovascular Institute Institute for Stem Cell Biology and Regenerative Medicine Department of Medicine Division of Cardiology Stanford University School of Medicine Stanford CA USA

Lauren M Gauthier Investigative Toxicology Drug Safety Research and Development Pfizer Inc Andover MA USA

Jean‐Charles Gautier Preclinical Safety Sanofi Vitry‐sur‐Seine France

Gary Gintant Integrative Pharmacology Integrated Science amp Technology AbbVie North Chicago IL USA

Christopher EP Goldring MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Warren E Glaab Systems Toxicology Investigative Laboratory Sciences Safety Assessment Merck Research Laboratories West Point PA USA

Brian D Guth Drug Discovery Support Boehringer Ingelheim Pharma GmbH amp Co KG Biberach (Riss) Germany DSTNWU Preclinical Drug Development Platform Faculty of Health Sciences NorthshyWest University Potchefstroom South Africa

Robert L Hamlin Department of Veterinary Medicine and School of Biomedical Engineering The Ohio State University Columbus OH USA

Alison H Harrill Department of Environmental and Occupational Health Regulatory Sciences Program The University of Arkansas for Medical Sciences Little Rock AR USA

Dylan P Hartley Drug Metabolism and Pharmacokinetics Array BioPharma Inc Boulder CO USA

Patrick J Hayden MatTek Corporation Ashland MA USA

James A Heslop MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Gregory Hinkle Bioinformatics Alnylam Pharmaceuticals Inc Cambridge MA USA

Mary Jane Hinrichs Biologics Safety Assessment MedImmune Gaithersburg MD USA

Kimberly M Hoagland Integrated Discovery and Safety Pharmacology Department of Comparative Biology and Safety Sciences Amgen Inc Thousand Oaks CA USA

Daniel Holder Biometrics Research Merck Research Laboratories West Point PA USA

Michelle J Horner Comparative Biology and Safety Sciences (CBSS) ndash Toxicology Sciences Amgen Inc Thousand Oaks CA USA

Chuchu Hu Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration (NCTRFDA) Jefferson AZ USA Zhejiang Institute of Food and Drug Control Hangzhou China

Peng Huang Institute of Bioengineering and Nanotechnology The Nanos Singapore

Wenhu Huang General Toxicology Drug Safety Research and Development Pfizer Inc La Jolla CA USA

Brandon D Jeffy Exploratory Toxicology Celgene Corporshyation San Diego CA USA

Paul Jennings Division of Physiology Department of Physiology and Medical Physics Medical University of Innsbruck Innsbruck Austria

Raymond Kemper Discovery and Investigative Toxicology Drug Safety Evaluation Vertex Pharmaceuticals Boston MA USA

Helena Kandaacuterovaacute MatTek In Vitro Life Science Laboratories Bratislava Slovak Republic

J Gerry Kenna Fund for the Replacement of Animals in Medical Experiments (FRAME) Nottingham UK

LIST OF CONTRIBUTORS xxiii

Patrick Kirby Drug Safety and Research Evaluation Takeda Boston Takeda Pharmaceuticals International Co Cambridge MA USA

Neil R Kitteringham MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Mitchell Klausner MatTek Corporation Ashland MA USA

Erik Koenig Molecular Pathology Takeda Boston Takeda Pharmaceuticals International Co Cambridge MA USA

Yue Ning Lam Institute of Bioengineering and Nanotechnoshylogy The Nanos Singapore

Lawrence H Lash Department of Pharmacology School of Medicine Wayne State University Detroit MI USA

Hank Lin Drug Safety Research and Development Pfizer Inc Cambridge MA USA

Hua Rong Lu Global Safety Pharmacology Janssen Research amp Development a division of Janssen Pharmaceutica NV Beerse Belgium

Karen M Lynch Safety Assessment GlaxoSmithKline King of Prussia PA USA

Jing Ying Ma Molecular Pathology Discovery Sciences Janssen Research amp Development LLC San Diego CA USA

Jonathan M Maher Discovery Toxicology Safety Assess ment Genentech Inc South San Francisco CA USA

Sherry J Morgan Preclinical Safety AbbVie Inc North Chicago IL USA

J Eric McDuffie Mechanistic amp Investigative Toxicology Discovery Sciences Janssen Research amp Development San Diego CA USA

Joseph Milano Milano Toxicology Consulting LLC Wilmington DE USA

Robin Mogg Early Clinical Development Statistics Merck Research Laboratories Upper Gwynedd PA USA

Rounak Nassirpour Biomarkers Drug Safety Research and Development Pfizer Inc Andover MA USA

Charlotte ML Nugues MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Andrew J Olaharski Toxicology Agios Pharmaceuticals Cambridge MA USA

B Kevin Park MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Mikael Persson Lundbeck Valby Denmark Currently at AstraZeneca Molndal Sweden

Amy C Porter Predictive Safety Testing Consortium (PSTC) Critical Path Institute (C‐Path) Tucson AZ USA

Patrick Poulin Associate Professor Department of Occupational and Environmental Health School of Public Health IRSPUM Universiteacute de Montreacuteal Montreacuteal Queacutebec Canada and Consultant Queacutebec city Queacutebec Canada

Christopher S Pridgeon MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Shashi K Ramaiah Biomarkers Drug Safety Research and Development Pfizer Inc Cambridge MA USA

Georg Rast Drug Discovery Support Boehringer Ingelheim Pharma GmbH amp Co KG Biberach (Riss) Germany

Ivan Rich Hemogenix Inc Colorado Springs CO USA

John‐Michael Sauer Predictive Safety Testing Consortium (PSTC) Critical Path Institute (C‐Path) Tucson AZ USA

Praveen Shukla Stanford Cardiovascular Institute Institute for Stem Cell Biology and Regenerative Medicine Department of Medicine Division of Cardiology Stanford University School of Medicine Stanford CA USA

Scott Q Siler The Hamner Institute Research Triangle Park NC USA

Aaron T Smith Investigative Toxicology Eli Lilly and Company Indianapolis IN USA

Dennis A Smith Independent Consultant Canterbury UK

Chris J Somps Investigative Toxicology Drug Safety Research and Development Pfizer Inc Groton CT USA

Manisha Sonee Mechanistic amp Investigative Toxicology Discovery Sciences Janssen Research amp Development LLC Spring House PA USA

Jaqueline Tarrant Development Sciences‐Safety Assessshyment Genentech Inc South San Francisco CA USA

xxiv LIST OF CONTRIBUTORS

Greet Teuns Janssen Research amp Development Janssen Pharmaceutica NV Beerse Belgium

Weida Tong Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration (NCTRFDA) Jefferson AZ USA

Katya Tsaioun Safer Medicine Trust Cambridge MA USA

Hugo M Vargas Integrated Discovery and Safety Pharmacology Department of Comparative Biology and Safety Sciences Amgen Inc Thousand Oaks CA USA

Allison Vitsky Biomarkers Drug Safety Research and Development Pfizer Inc La Jolla CA USA

Elizabeth G Walker Predictive Safety Testing Consortium (PSTC) Critical Path Institute (C‐Path) Tucson AZ USA

Yvonne Will Investigative Toxicology Drug Safety Research and Development Pfizer Inc Groton CT USA

Bettina Wilm Department of Cellular and Molecular Physiology The Institute of Translational Medicine The University of Liverpool Liverpool UK

Joseph C Wu Stanford Cardiovascular Institute Institute for Stem Cell Biology and Regenerative Medicine Department of Medicine Division of Cardiology Stanford University School of Medicine Stanford CA USA

Joshua Xu Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration (NCTRFDA) Jefferson AZ USA

Xu Zhu Immunotoxicology Center of Emphasis Drug Safety Research and Development Pfizer Inc Groton CT USA

Gina M Yanochko Investigative Toxicology Drug Safety Research and Development Pfizer Inc La Jolla CA USA

Ke Yu Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration (NCTRFDA) Jefferson AZ USA

Tanja S Zabka Development Sciences‐Safety Assessment Genentech Inc South San Francisco CA USA

Fang Zhang MRC Centre for Drug Safety Science Department of Molecular and Clinical Pharmacology The Institute of Translational Medicine University of Liverpool Liverpool UK

Xiaobing Zhou National Center for Safety Evaluation of Drugs Beijing China

Daniele Zink Institute of Bioengineering and Nanoteshychnology The Nanos Singapore

xxv

FOREWORD

Discovering drugs with good efficacy and safety profiles is a very complex and difficult task The magnitude of the challenge is best illustrated by the size of the research and development (RampD) investments needed for driving a new molecular entity (NME) to approval Multiple factors conshytribute to this level of difficulty let alone the fact that biology and diseases are by themselves extremely complex There is good consensus that safety and efficacy represent the two most important aspects for success and are not surprisingly considered the two major causes for failure in development Trying to predict safety and toxicity in humans is not a recent area of interest but has been emphasized much earlier in the drug discovery process over the past decade This makes a lot of business sense given that even minor improvements in toxicity‐related attrition at the development stage translate in significant overall increases in RampD productivity and meaningful benefit to patients

Toxicologists in their effort to predict toxicity have always tried to develop new models or technologies In particular a large volume of scientific literature covers charshyacterization of in vitro models for toxicology applications In spite of experimental inconsistencies among users and across published studies there is no doubt that progress has been made in understanding the characteristics of those models Some have clear and often insurmountable limitations but others have sufficiently robust characteristics to be useful for small‐molecule lead optimization or for mechanistic investishygations of toxic effects However practices and implementashytions across companies are quite different and any opportunity for scientists to share their experience and recommendations can only help move the field forward One common theme across companies however is the effort to move safety assessment earlier in the drug discovery and development

process at least at the lead optimization stage but preferenshytially as early as target selection

In the pharmaceutical industry toxicology support at the discovery stage is a different approach from toxicology activities at the development stage The role of the discovery toxicologist is to participate in collaboration with other functions in the selection of molecules with optimal properties (eg physicochemical pharmacokinetic pharshymacological safety) but also in the prioritization of therapeutic targets with a reasonable probability of success The latter requires scientists to develop a fundamental undershystanding of the biology of the target not only in terms of potential therapeutic benefits but also in terms of potential safety liabilities In the past this aspect was a relatively low priority in most pharmaceutical companies with most efforts focused on pharmacology and medicinal chemistry However recent experience in most companies indicates that target‐related safety issues are more frequent than previously thought and can be development limiting This becomes even more relevant given the improved ability of medicinal chemists and toxicologists to rapidly and reliably eliminate molecules with intrinsic reactive properties

Beyond target biology various tools are currently used for compound optimization for absorption distribution metabolism and excretion (ADME) pharmacokinetics and toxicology properties as reviewed in the first part of this comprehensive book These tools include among others in silico models high‐throughput binding assays cell‐based assays with biochemical impedance or high‐content imaging endpoints or lower‐throughput specialized assays such as the Langendorff assay or three‐dimensional in vitro models Irrespective of their level of complexity and sophisshytication all these assays must be interpreted in the context of

xxvi FOREWORD

all other relevant data to properly influence compound selection and optimization Hence the main challenge for toxicologists supporting discovery projects is usually not data generation but mostly interpretation and communicashytion of these data in a timely manner This implies that data need to be generated at the appropriate time to be useful and interpreted in the context of large numbers of other data points To address these issues a robust discovery toxicology organization needs to have access to the appropriate logisshytical support as well as informatics and computational tools an aspect that is currently often not emphasized enough In contrast models focused on predicting toxicity for specific tissues are difficult to use in a prospective manner but can be extremely useful for optimization against a target organ toxicity already identified in animals with lead molecules

Animal models do not predict all possible toxic events in humans but it is important to keep in mind that their negashytive predictive value is extremely high As such they fulfill their main objective very well In other words they allow drug developers to test novel molecules in humans without undue safety risks This is best illustrated by the extremely rare major safety issues encountered in first‐in‐human studies Therefore to further improve toxicity prediction one valuable approach is to identify the gaps in the current nonclinical models used for toxicity prediction and try to fill these Solutions include for instance the use of nontradishytional animal models such as genetically engineered or diseased rodent models the rapidly evolving stem cell field with the development of human induced pluripotent stem cell (iPSC)‐based systems the development of safety bioshymarkers with better performance characteristics compared to current biomarkers or the use of information‐rich technolshyogies that help bring mechanistic clarity

The past decade has witnessed an increased number of precompetitive consortia such as the Predictive Safety

Testing Consortium and the Innovative Medicine Initiative which have fueled the pace of research progress in predictive toxicology These precompetitive collaborations represent ideal forums to share ideas and experience but also to test in an efficient and systematic way new methods for toxicity prediction These collaborative efforts will undeniably accelshyerate the development of novel models or biomarkers that will ultimately benefit patients and support animal welfare efforts Companies and scientists should be encouraged to be actively involved in those forums

The book edited by my colleagues Drs Yvonne Will J Eric McDuffie Andrew J Olaharski and Brandon D Jeffy provides a very comprehensive view of the current state of the art of discovery toxicology in the pharmashyceutical industry The various components of discovery toxicology are presented in a coherent and logical manner through a series of parts and chapters authored by renowned contributors combining impressive cumulative years of experience in the field These chapters accurately reflect the current thinking and toolbox available to the toxicologist working in the pharmaceutical industry and also reflect on future possibilities The authors and editors should be applauded for their efforts to comprehensively and didactically share this knowledge This book will undoubtedly become a reference for all of us involved in the toxicological assessment of pharmaceutical experimental compounds

Eric AG Blomme DVM PhD Diplomate of the American College of Veterinary Pathologists

Senior Research Fellow ViceshyPresident of Global Preclinical Safety

AbbVie IncNorth Chicago IL USA

E‐mail address ericblommeabbviecom

Part I

INtrODUCtION




Edited by











10 9 8 7 6 5 4 3 2 1

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FOREWORD xxv













CONTENTS

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viii CONTENTs












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CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















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animal to Human 279

CONTENTs xiii

















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CONTENTs xix

















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aBBREVIaTIONS 540


INDEx 543

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Part I

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Edited by











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CONTENTS

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viii CONTENTs












References 152




CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















xii CONTENTs






















animal to Human 279

CONTENTs xiii

















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CONTENTs xv














xvi CONTENTs












References 439



CONTENTs xvii















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CONTENTs xix

















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aBBREVIaTIONS 540


INDEx 543

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Part I

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10 9 8 7 6 5 4 3 2 1

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vi CONTENTs


















CONTENTs vii











References 77








viii CONTENTs












References 152




CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















xii CONTENTs






















animal to Human 279

CONTENTs xiii

















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CONTENTs xv














xvi CONTENTs












References 439



CONTENTs xvii















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CONTENTs xix

















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aBBREVIaTIONS 540


INDEx 543

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v


FOREWORD xxv













CONTENTS

vi CONTENTs


















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viii CONTENTs












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CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















xii CONTENTs






















animal to Human 279

CONTENTs xiii

















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CONTENTs xv














xvi CONTENTs












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CONTENTs xvii















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CONTENTs xix

















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References 525



aBBREVIaTIONS 540


INDEx 543

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FOREWORD






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INtrODUCtION

vi CONTENTs


















CONTENTs vii











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viii CONTENTs












References 152




CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















xii CONTENTs






















animal to Human 279

CONTENTs xiii

















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CONTENTs xv














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aBBREVIaTIONS 540


INDEx 543

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CONTENTs vii











References 77








viii CONTENTs












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CONTENTs ix









References 170










x CONTENTs




















1551 In Vitro 2221552 In Vivo 223

References 223

CONTENTs xi




















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animal to Human 279

CONTENTs xiii

















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CONTENTs xv














xvi CONTENTs












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INDEx 543

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viii CONTENTs












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References 170










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References 223

CONTENTs xi




















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INDEx 543

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CONTENTs ix









References 170










x CONTENTs




















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References 223

CONTENTs xi




















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CONTENTs xiii

















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Thumbnail - Startseite...9.7 assessment of Large Versus small Molecules in CV sP 147 9.7.1 Introduction147 9.7.2 CV sP Evaluation 147 9.8 Patients do not Necessarily Respond to Drugs